Palatable Suspending Vehicle for Pharmaceutical Ingredients

ABSTRACT

The invention relates to a liquid vehicle that can be used to create suspensions and/or solutions of liquid or powdered medications. The vehicle is thixotropic and has improved stability and rheologic characteristics. Vehicles of the invention include an aqueous medium and a suspending agent comprising a polysaccharide having at least 50% glucose repeating saccharide units and at least 90% alpha linkages. The polysaccharide can be a starch, modified starch, or glycogen. The aqueous medium and individual components of the vehicle provide a palatable and easily ingested drug preparation. The invention also provides a vehicle containing an aqueous medium, suspending agent comprising a polysaccharide having at least 50% glucose repeating saccharide units and at least 90% alpha linkages, buffer, and artificial sweetener, the combined suspending vehicle having a pH of about 3 to about 10 and an osmolality of 300 mOmsol or less.

This application is a continuation of U.S. application Ser. No.11/203,520, filed Aug. 12, 2005, entitled “PALATABLE SUSPENDING VEHICLEFOR PHARMACEUTICAL INGREDIENTS”, which claims priority under 35 U.S.C.§119(e) to U.S. Provisional Application Ser. No. 60/601,326, filed onAug. 13, 2004, entitled “PALATABLE SUSPENDING VEHICLE FOR PHARMACEUTICALINGREDIENTS”, both of which are hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The invention relates to a liquid vehicle that can be used to createsuspensions and/or solutions of a solid or liquid medicament. Thevehicle is adapted for easy blending, finished product stability, andsafety.

BACKGROUND OF THE INVENTION

There is often a need to administer solid medications in oral liquidforms to patients. These patients include adults who cannot swallowsolid dosage forms, infants and children, nonambulatory patients withnasogastric tubes, geriatric patients, and animals. In a typicalpreparation, a medication available in a tablet or bulk powder form isfinely ground, wetted with a wetting agent, and then combined slowlywith a liquid vehicle. This technique is flexible and provides a methodto treat a patient with a variety of medicaments in alternative dosageforms.

Ideally, a liquid suspending vehicle is thixotropic, has a measurableyield value or is a pseudoplastic power law liquid with a low flowindex, is shear thinning, prevents solid particles too large to besuspended from forming a hard cake in the vehicle, is physiologicallycompatible and results in minimal gastric impact, is resistant tochanges induced by the addition of unknown chemical substances, providesa chemically inert environment, and has a pleasant or neutral flavor andmouth-feel (Thompson, J. E., A Practical Guide to Contemporary PharmacyPractice, Lippincott Williams & Wilkins, Baltimore, Md., 1998, p. 28.1).There are a variety of products currently available whose primaryfunction is to serve as a liquid vehicle for compounding extemporaneoussolutions or suspensions. None of the currently available products meetall of the criteria set forth in Thompson (Id.).

Most products currently available employ one or more suspending agents,such as agar, alginic ac, activated attapulgite, bentonite, carbomer,carboxymethycellulose (calcium and sodium salts), carrageenan,microcrystalline cellulose, dextrin, gelatin, guar gum,hydroxypropylmethylcellulose, methylcellulose, pectin, poloxamer,polyoxyethylene oxide, polyvinyl alcohol, povidone, propylene glycolalginate, silicon dioxide, sodium alginate, tragacanth, and xanthan gum(Allen, L. V. Jr., The Art, Science, and Technology of PharmaceuticalCompounding, American Pharmacy Association, Washington, D.C., 1998, p.169).

While these products are designed to provide permanent suspensions, theysuffer from shortcomings including: sedimentation of ingredients addedto the suspension; difficulty resuspending sedimented ingredients;hydrolysis of the suspending agent; deactivation, precipitation, orcoagulation of the suspending agent due to chemical, electrolyte, orcation sensitivities and/or physical changes such as shear ortemperature; and deactivation, precipitation, or coagulation byamphiphilic or detergent-like molecules. In addition, many of thepreviously formulated liquid suspending vehicles are hyperosmotic,incompatible with one or more frequently compounded medications, and/orhave a bulk laxative effect.

Clearly, a substantial need exists for an improved liquid vehicle forpreparing medicinal suspensions or solutions.

BRIEF DISCUSSION OF THE INVENTION

The invention relates to a liquid vehicle that can be used by apharmacist, physician, dentist, veterinarian, or other healthprofessional to suspend, dissolve, or disperse a drug to provide aliquid suspension suitable for human or animal ingestion. The vehiclesof the invention can serve as the basis for a palatable and safecompounded or manufactured medicinal preparation.

A vehicle of the invention typically contains an aqueous medium and asuspending agent comprising a polysaccharide having at least 50% glucoserepeating saccharide units and at least 90% alpha linkages. Suchsuspending agents typically include starch, modified starch, orglycogen. In an embodiment, the vehicle comprises about 1% to about 15%suspending agent by weight.

Some embodiments of the invention contain buffers, sweeteners,preservatives, antimicrobial agents, anti-oxidants, flavoring agents,flavor enhancers, colorants, texture modifiers, surfactants, and/ordefoaming agents. The sweetener can be a nutritive or non-nutritiveartificial sweetener. Examples of suitable artificial sweeteners includesucralose, saccharin, aspartame, stevia, and acesulfame K. In anembodiment, a vehicle of the invention comprises about 1% or lessartificial sweetener by weight. A vehicle of the invention can beunbuffered or buffered to a pH of about 3 to 10. In some embodiments,the pH of the vehicle is buffered to mimic the pH of the stomach.

In an embodiment, a vehicle of the invention contains an aqueous medium,suspending agent comprising a polysaccharide having at least 50% glucoserepeating saccharide units and at least 90% alpha linkages, anartificial sweetener, and a buffer. The suspending agent can contain amodified or unmodified starch and the pH of the vehicle can be fromabout 3 to about 10.

The vehicles of the invention are compatible with most drugsadministered orally. A drug in powder form or pill, capsule, or othersolid drug product can be rendered into a fine powder form and combinedwith a vehicle of the invention. Vehicles of the invention can becombined with about 0.01 to about 100,000 mg of drug or inactiveingredient per each 100 ml of vehicle. Typical concentrations are fromabout 1 to about 100 mg of drug per ml of vehicle.

The vehicles of the invention have improved rheological characteristicsand stability. Preferably, a vehicle of the invention is thixotropic,and has a yield value greater than 0 or, at shear rates less than about1 sec⁻¹, the flow index of the vehicle decreases or remains constant asthe shear rate decreases. In an embodiment, the vehicle has a yieldvalue of about 0.01 dynes/cm² to about 600 dynes/cm². A vehicle of theinvention can maintain its form and suspending function after chemicalor physical perturbation. A vehicle of the invention can tolerate avariety of perturbations including, but not limited to, changes in ionicstrength, Lewis acidity/basicity of added ingredients; physicalconditions of preparation including shearing, freezing and heating, thepresence of metals and/or chelating agents, and the presence of soap,soap-like, or detergent type molecules. Embodiments of the inventionallow for easy and quick resuspension of sedimented ingredients. In anembodiment, a drug or inactive ingredient can be suspended orresuspended in a vehicle of the invention without high shear mixing.

The osmolality, pH, and carbohydrate or natural sweetener content can becontrolled in a vehicle of the invention to maintain physiologicalcompatibility with a patient. Hyperosmotic preparations (preparationswith osmolality greater than 300 mOsmol) can induce saline laxation in apatient which results in some level of dehydration for the patient.Infants, small children, and the elderly are most sensitive to thisdehydration.

Embodiments of the invention can be formulated with very low osmolality.This aspect of the invention enables a compounding pharmacist, forexample, to add drugs and/or inactive ingredients in significantconcentrations without concern about hypertonicity in the finalpreparation. A vehicle of the invention can be formulated with anosmolality of about 300 mOsmol or less. In an embodiment, the osmolalityof the vehicle is 50 mOsmol or less. In another embodiment, theosmolality of the vehicle is about 30 to about 40 mOsmol. In yet anotherembodiment, the osmolality of a vehicle of the invention is sufficientlylow such that the osmolality of the final preparation does not exceed300 mOsmol after addition of a drug(s) and inactive ingredients.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows shear stress of an embodiment of the invention (VE1) and a1:1 mixture of ORA-SWEET SF® and ORA-PLUS® (OO) at shear rates from 0.1to 100.

FIG. 2 shows shear stress of an embodiment of the invention (VE1) and a1:1 mixture of ORA-SWEET SF® and ORA-PLUS® (OO) at shear rates from 0.01to 1.

FIG. 3 shows shear stress of an embodiment of the invention (VE1) and a1:1 mixture of ORA-SWEET SF® and ORA-PLUS® (OO) as shear rate issteadily increased and then decreased. The shear stress of VE1 isplotted against the left y-axis and the shear stress of OO is plottedagainst the right y-axis.

FIG. 4 shows the viscosity of an embodiment of the invention (VE1) and a1:1 mixture of ORA-SWEET SF® and ORA-PLUS® (OO) over time.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to aqueous vehicles that can be used to suspend,dissolve, or disperse a liquid or solid medicament. The term“medication”, “medicament”, or “drug” as used herein means a productintended for use in the diagnosis, cure, mitigation, treatment, orprevention of a disease in a human or animal. Over-the-counter andprescription drugs, medications, or medicaments including, but notlimited to, vitamins, cold medications, allergy medications, herbalmedications, analgesics, pharmaceuticals, pharmaceutical compounds,active and inactive pharmaceutical ingredients, and nutriceuticals areincluded within the scope of the term “drug.” A drug or drug product canbe in liquid form, powder form, or solid form including, but not limitedto, pills, tablets, and capsules. In some embodiments, the drug,medication, or medicament, is a solid or liquid oral dosage form. In atypical preparation, a medication available in a tablet or bulk powderform is finely ground, wetted with a wetting agent, and then combinedslowly with a liquid vehicle. This technique is flexible and provides amethod with which to administer a variety of medicaments orally in analternative dosage form, such as a liquid, to patients.

A. Formulations and Rheology

An agent that can effectively suspend a drug, medication, or medicamentinto the vehicle is used to formulate the vehicles of the invention. Avehicle of the invention includes an aqueous medium and a suspendingagent comprising a polysaccharide having at least 50% glucose repeatingsaccharide units and at least 90% alpha linkages. Surprisingly, we havefound that an aqueous vehicle comprising such a suspending agentdisplays superior rheologic characteristics compared with previouslyformulated suspending vehicles containing cellulosic-based suspendingagents. Suspending agents comprising a polysaccharide having at least50% glucose repeating saccharide units and at least 90% alpha linkagestypically include starch or glycogen. The starch can be unmodified ormodified. In an embodiment, the balance of the polysaccharide comprisesa C₆ saccharide unit.

In an embodiment, the vehicle comprises about 1% to about 15% suspendingagent by weight. In another embodiment, the vehicle comprises about 2%to about 10% suspending agent by weight. In another embodiment, thevehicle comprises about 2% to about 7% suspending agent by weight. Inyet another embodiment, the vehicle comprises about 4% to about 6%suspending agent by weight.

A number of references have tabulated pharmaceutical suspending agents;however, none of these references discloses starch as a suspending agent(USP/NF: The Official Compendia of Standards, 27^(th) and 22^(nd) eds.,United States Pharmacopeial Convention, Inc., Rockville, Md., 2004.;Thompson, J. E., Davidow L., A Practical Guide to Contemporary PharmacyPractice, 2^(nd) ed., Lippincott Williams & Wilkins, Baltimore, Md.,2004, p. 28.1-28.23; Allen, L. V. Jr., The Art, Science, and Technologyof Pharmaceutical Compounding, 2^(nd) ed., American PharmacyAssociation, Washington, D.C., 2002, p. 251; Remington: The Science andPractice of Pharmacy, Genarro A. R. ed., 20^(th) ed., LippincottWilliams & Wilkins, Philadelphia, Pa., 2000, pp. 744, 321; Allen, L. V.Jr., Int. J. Pharm. Comp., 2001, 5:294; Allen, L. V. Jr., Int. J. Pharm.Comp., 2001, 5:65; Chan, D. S., Int. J. Pharm. Comp., 2001, 5:9; Int. J.Pharm. Comp., 1997, 2:86; Palmer, H. A., Int. J. Pharm. Comp., 1998, 2;Allen, L. V. Jr., Int. J. Pharm. Comp., 1999, 3:479; Ansel H. C., AllenL. V. Jr., Popovich N. G., Pharmaceutical Dosage Forms and Drug DeliverySystems, 7^(th) ed., Lippincott Williams & Wilkins, Philadelphia, Pa.,1999, p. 346).

In an embodiment, the suspending agent is comprised of starch. Starch isa well-known material used in a variety of nutritive and non-nutritiveapplications. Starches can be obtained from a variety of plant sourcesincluding grains (such as wheat, corn, or rice), roots and tubers (suchas tapioca, potato, and cassava), and fruits and vegetables (such asbanana, tomato, and pumpkin). The nature of the starch materials fromeach individual plant source can exhibit different properties. Starchestend to be dispersible or suspendable in aqueous liquids to providethickening properties. Since colloidal properties of starch and modifiedstarches are primarily nonionic, the electrolytic sensitivity is lowerthan other common formulations, and in particular, charged versions ofmodified cellulosic suspending agents.

The starch can be derivatized or modified. The starch can be modified bycrosslinking, substitution, hydrolysis, or dextrination. In anembodiment, modification includes capping the dangling hydroxy groups toform ethers or esters. Modified starches include, but are not limitedto, starch acetate, starch phosphate, starch succinate, hydroxy ethylstarch, hydroxy propyl starch, cationic starches, oxidized starches anddextrin compositions. Preferred starches for use in the vehicles of theinvention include modified starches that provide substantial thickeningcharacteristics to enable the liquid vehicles of the invention tomaintain a drug, medication, or medicament in suspension and modifiedstarches that are compatible with the pH and osmolality of the desiredend product.

In an embodiment, the vehicle comprises about 1% to about 15% starch ormodified starch by weight. In another embodiment, the vehicle comprisesabout 2% to about 10% starch or modified starch by weight. In anotherembodiment, the vehicle comprises about 2% to about 7% starch ormodified starch by weight. In yet another embodiment, the vehiclecomprises about 4% to about 6% starch or modified starch by weight. Insome embodiments, the starch is granular. In these embodiments, thegranules can comprise a diameter of about 1 μm to about 150 μm.

In an embodiment, the starch comprises an amylose:amylopectin ratio ofabout 10%:90% to about 60%:40% by weight. In another embodiment, thestarch comprises an amylose:amylopectin ratio of about 15%:80% to about40%:60% by weight. In yet another embodiment, the starch comprises anamylose:amylopectin ratio of about 20%:80% to about 30%:70% by weight.

In an embodiment, the starch comprises a molecular weight of about 1 kDto about 10,000 kD. In another embodiment, the starch comprises amolecular weight of about 1,000 kD to about 10,000 kD. In anotherembodiment the starch comprises a molecular weight of about 2,000 kD toabout 8,000 kD. In another embodiment, the starch comprises a molecularweight of about 3,000 kD to about 5,000 kD. In another embodiment, thestarch comprises a molecular weight of about 20 kD to about 1,000 kD. Inyet another embodiment, the starch comprises a molecular weight of about20 kD to about 600 kD.

Manufacturers of natural and modified starches useful in the aqueoussuspending vehicles of the invention include, but are not limited to,Cargill (Minneapolis, Minn.), National Starch and Chemical (Bridgewater,N.J.), Grain Processing Corporation (Muscatine, Iowa), Penford FoodIngredients (Englewood, Colo.), and A. E. Staley Manufacturing Company(Decatur, Ill.). Others manufacturers are known. The starch can be afood grade, reagent grade, ACS grade, pharmaceutical grade, or othersuitable grade starch. Trade names of starches for use in vehicles ofthe invention include, but are not limited to, Inscosity 658 (GrainProcessing Corporation, Muscatine, Iowa), Pure-Set B950 and B965 (GrainProcessing Corporation, Muscatine, Iowa), Pure-Gel B992 and B994 (GrainProcessing Corporation, Muscatine, Iowa), and STA-Rx (A. E. StaleyManufacturing Company (Decatur, Ill.). Other natural and modifiedstarches are known.

One review reveals that the primary design goal of aqueous vehicles isto obtain a permanent suspension (see Meyer and Cohen, J. Soc. CosmeticChemists, 1959, 10:143; Miller, Pharm. J. Nov. 26, 1983, p. 629). Inorder for a suspension of a medicament to be considered permanent,suspended solid particles cannot visibly settle on the timescale of theevaluation. There are several mechanisms by which this can beaccomplished. An aqueous vehicle can, for example, be thixotropic (theviscosity of the vehicle increases at rest), have a yield value, or be apseudoplastic power law fluid having high viscosity at sedimentationshear rates.

A suspending vehicle of the invention preferably is thixotropic (theviscosity of the vehicle increases at rest), and has a yield valuegreater than 0 or is a pseudoplastic power law fluid. In an embodiment,the suspending vehicle is thixotropic and has a yield value greater than0. The yield value can be from about 0.01 dynes/cm² to about 600dynes/cm², from about 1 dynes/cm² to about 600 dynes/cm², from about0.01 dynes/cm² to about 300 dynes/cm², from about 0.01 dynes/cm² toabout 200 dynes/cm², from about 0.01 dynes/cm² to about 100 dynes/cm²,from about 0.01 dynes/cm² to about 50 dynes/cm², or from about 0.01dynes/cm² to about 10 dynes/cm². In an embodiment, the yield value isgreater than 0 but equal to or less than 600 dynes/cm².

In another embodiment, the suspending vehicle is thixotropic and apseudoplastic power law fluid. A power law fluid behaves in apredictable way with respect to well-defined shear rate and shearstress. The viscosity of a substance is given by η=τ/γ, where η isviscosity (in units of poise), τ is shear stress (in units ofdynes/cm²), and γ is shear rate (in units of sec⁻¹). Over some range ofshear rate value, the shear stress (and indirectly the viscosity) of apower law fluid is given by τ=kD^(n), where k is known as theconsistency index, D is the shear rate, and n is the flow index. A powerlaw fluid with a higher consistency index will have a greater viscosityat a given shear rate. In an embodiment, a vehicle of the inventioncomprises a consistency index from about 400 to about 30,000 centipoise.

Power law fluids with flow indexes of less than 1 are pseudoplastic. Forthese fluids, the closer the flow index is to zero, the greater theviscosity becomes at low shear rates. There are two ranges of shearrates that are of primary interest for an aqueous suspending vehicle: 1)shaking and pouring of the vehicle are rheological events generatingshear rates of about 10¹ to 10³ sec⁻¹, and 2) sedimentation (settling ofsolid particles from suspension) generates shear rates of about 10⁻⁶ to10⁻⁴ sec⁻¹. In some embodiments, at a shear rate of less than about 1sec⁻¹, the flow index of a vehicle of the invention decreases or remainsconstant as the shear rate decreases. In an embodiment, a vehicle of theinvention comprises a flow index of less than about 0.8 at a shear rateof less than about 1 sec⁻¹.

A suspending vehicle of the invention can be buffered or unbuffered.Preferably the buffer is generally recognized as safe (GRAS) by the U.S.Food and Drug Administration. The pH of the liquid vehicle of theinvention can be adjusted to a physiological pH by measuring the pH of abatch of the material and either adding acid to lower pH or adding baseto raise pH. The buffer can include an organic acid, inorganic acid, orsalts thereof. Examples of suitable acids include, but are not limitedto, malic acid, citric acid, ascorbic acid, tartaric acid, adipic acid,lactic acid, furmaric acid, maleic acid, acetic acid, phosphoric acid,or salts thereof, singly or in combination. Examples of suitable basesinclude, but are not limited to, calcium and sodium carbonate, calciumand sodium bicarbonate, and salts of the organic or inorganic acidslisted above. The above listed compatible acids can be used for pHreduction; however, the increase in pH can be obtained through the useof small amounts of food grade inorganic bases including, but notlimited to, metal hydroxides or basic salts thereof including sodiumhydroxide solution, potassium hydroxide solution, ammonium hydroxidesolution, ammonium chloride solution, sodium citrate, sodium dihydrogenphosphate, etc. Such pH modifying or buffering agents are well known inthe art and can be applied as needed.

The pH of a vehicle of the invention can buffered or unbuffered to a pHof about 3 to about 10. In some embodiments, the pH is buffered to a pHof about 3 to 7. In some embodiments, the pH is buffered to a pH ofabout 3 to 5. In some embodiments, the pH is buffered to about 4.2. Manyorally administered drugs, in liquid or solid form, are stable atstomach pH (typically a pH of about 3 to about 5). By mimicking thenatural pH of the stomach without high concentration of acids, a vehicleof the invention can provide a more physiologically correct environmentfor orally ingested drugs. The moderate sour flavor provided by a pH ofabout 3 to about 5 has an antagonistic effect with bitter notes, whichare commonly rejected notes introduced by medications or preservativestypically incorporated into suspending vehicles. Microbial growth isalso suppressed at a pH of about 3 to about 5, allowing us to decreasequantities of preservatives in the vehicle that can impart a bittertaste. A pH in the range of about 3 to about 5 also allows us to usebenzoic acid and sorbic acid for preservation in low quantities due tothe bactericidal nature of the lower pH and the higher quantity ofprotonated acid in the vehicle. A vehicle of the invention can also belightly buffered (10 to 100 mMolar) to keep the osmolality of thevehicle low.

A suspending vehicle of the invention can include natural or artificialsweeteners. The sweetness and/or taste of these artificial sweetenerscan be modulated somewhat by the addition of small amounts of nutritivesweeteners. In an embodiment, the amounts of such mono- anddi-saccharide nutritive sweeteners such as fructose, high fructose cornsyrup and glucose are maintained at low levels to avoid altering thephysiological compatibility of the vehicle. Typical natural nutritivesweeteners include, but are not limited to, glucose, high fructose cornsyrup, starch hydrolysates, hydrogenated starch hydrolysates, corn syrupsolids, sucrose, mannitol, sorbitol, glycerol and other mono- ordi-saccharide nutritive sweeteners. The vehicles of the inventiongenerally contain less than 1% w/v, preferably less than 0.1% w/v, morepreferably less than 0.075% w/v of such natural sweeteners, but cancontain an effective sweetening amount of non-nutritive artificialsweetener. Such sweeteners generally, on a gram by gram basis, have asweeter character than natural nutritive sweeteners. Typically availablesweeteners include, but are not limited to, aspartame(L-asparatryl-L-phenylalanine methyl ester), saccharin(1,2-benzisothiazol-3(2H)-one-1,1-dioxide), stevia, acesulfame K(5,6-dimethyl-1,2,3-oxathiazin-4(3H)-one-2,2 dioxide, potassium salt),sucralose(1,6-Dichloro-1,6-dideoxy-beta-D-fructofuranosyl-4-chloro-4-deoxy-alpha-D-galactopyranoside),and mixtures thereof. Other artificial sweeteners are known. Other knownsweeteners that may not be readily available in all countries include,but are not limited to, cyclamate salts, aceslfame, glycyrrhizinate andmixtures thereof. Such a nutritive and non-nutritive sweetening agentscan be modified by other compositions to balance sweetness.

The flavor of the liquid vehicle of the invention can be modified toenhance patient acceptance. Commonly available flavorings, aromaticmaterials, resins and other compositions including both natural andsynthetic products can be added to the vehicle. Such materials include,but are not limited to, spearmint flavor, cinnamon flavor, wintergreenflavor, peppermint, eucalyptus, thyme, sage, almond, fruit flavors, andother compatible materials.

The liquid vehicle of the invention can include an acid material thatadds a tart or citrus flavor and can aid in the regulation of theosmolality of the substance. Such acids that are typically food gradeand physiologically compatible include acids such as lactic, citric,glycolic, maleic, succinic, tannic, acetic, ascorbic, fumeric,phosphoric, tartaric, gluconic and the like. Citric acid, maleic acid,ascorbic acid and other related food grade acids are preferred, eithersingly or in combination in the liquid vehicles of the invention.Surfactant material can be helpful in blending the liquid vehicle,blending the liquid vehicle with the medicament, and increasing thecompatibility of the liquid vehicle with the patient.

Surfactants or surfactant-like molecules can also act as defoamingagents. Such agents include, but are not limited to, anionicsurfactants, non-ionic surfactants, amphoteric surfactants and others.Useful surfactants include, for example, sulfonate and sulfatesurfactants, polyethylene glycols, polyethylene glycol esters,polyethylene glycol ethers, sorbitan materials known as Span™ and Tween®materials and polyalkylene oxide surfactants also known as pluronic orreverse pluronic surfactants. Siloxane polymers, such as simethicone,are useful for reducing foaming that is likely to occur when the vehicleis shaken or vigorously agitated. These materials are typically added atrelatively low amounts and can be used at about 0.001 to about 0.5 gramsof the agent per 100 milliliters of the liquid vehicle. These materialsalso assist in wetting hydrophobic solids added to the vehicle of theinvention.

Food grade solvent materials can help increase the compatibility of theliquid vehicle with a medicament and enhance patient compatibility andoverall product quality. Such solvents typically include aliphaticalcohols such as methanol and ethanol, dimethylsulfoxide, and others.

The liquid vehicles of the invention may be formulated by adequatelycombining pharmacologically acceptable carriers or media including, butnot limited to, sterilized water, physiological saline, vegetable oil,emulsifiers, suspensions, surfactants, stabilizers, flavoring agents,preservatives, and texture modifiers.

The liquid vehicles of the invention can contain preservativecompositions including, but not limited to, benzyl alcohol, parabens,benzoate salts and other well known stabilizing materials. Preservativesthat occur naturally in fruits and vegetables can be used in a vehicleof the invention in the same concentration as they occur in nature. Inan embodiment, the preservative comprises benzoic acid and sorbic acid.The effectiveness of sorbic and benzoic acids as preservatives can beenhanced by buffering the vehicle to a pH of about 4 to about 5. Inanother embodiment, the preservative comprises benzoic acid withoutsorbic acid. In a preferred embodiment, the liquid vehicle contains aminimum quantity of preservative while maintaining product freshness,including antimicrobial and antimycotic effectiveness. In someembodiments, the vehicle of the invention is sterile. In theseembodiments, preservatives can be optionally included in the vehicle ofthe invention.

A general formulation for an embodiment of a liquid vehicle of theinvention contains the following:

TABLE 1 Ingredient Range (percent by weight) Starch <15% Sweetener <20%Buffer <10% Defoaming agent  <4% Preservative  <5% Dye  <3% Flavoring <5% Water >70%

In another embodiment, a vehicle of the invention contains from about 2%to about 6% starch, from about 0.01% to about 1% nutritive ornon-nutritive, potent sweetener, 0.1-2.5% buffer, and 0.01 to 1%preservative.

B. Stability

It is impossible to anticipate every possible pharmaceutically active orinactive ingredient that may be compounded into a suspending vehicle ofthe invention. Many drugs can affect the suspending properties of thepreparation adversely. Suspending agents can have sensitivities to avariety of conditions, including, but not limited to, pH of thecompounded solution; the ionic strength of the compounded solution;Lewis acidity/basicity of the added ingredients/solution; physicalconditions of preparation, including shear and temperature; the presenceof metals and/or chelating agents; the presence of soap, soap-like, ordetergent type molecules. Powders that settle in finished compoundedproducts are prone to ‘packing’, where the powder forms a tight cake atthe bottom (or top, depending on the density) of the preparation andother problems.

Vehicles of the invention preferably maintain their form and suspendingfunction after chemical or physical perturbation. A vehicle of theinvention can tolerate a variety of perturbations including, but notlimited to, changes in ionic strength, Lewis acidity/basicity of addedingredients; physical conditions of preparation including shearing,freezing, and heating, the presence of metals and/or chelating agents,and the presence of soap, soap-like, or detergent type molecules.

Powders insoluble in a suspending agent can sediment visibly with time.When a solid is ground before adding it to a suspending vehicle, adistribution of particle sizes occurs. Larger particles will settle morequickly than others in a given vehicle. Ideally, the viscosity of anaqueous suspending vehicle is high enough to sufficiently maintainsolids in suspension. However, the vehicle must also be able to bepoured easily. For any vehicle, there exists a particle size and densityaccording to Stokes' law that will visibly sediment from the vehiclewith time. This leads to inhomogeneous (heterogeneous) preparations ofthe incorporated drug or inactive ingredients, which, if not vigorouslyshaken, can result in inaccurate dosing.

Solids that settle in a finished compounded product are prone topacking, where the solids form a tight cake at the bottom or top of thepreparation (depending on density). Depending upon how strong thispacking is, the product may not be able to be made homogenous (as it waswhen it was first prepared) by simple shaking of the preparation. Avehicle that prevents sedimented particles from packing tightly isdesirable, therefore a homogenous suspension can be reconstituted bysimply shaking it.

Embodiments of the invention allow for resuspension of sedimentedingredients. Starch has a unique structure on the 1 to 150 micron scale.When dried, the granules are hard, with little friction betweengranules, which is the reason it is often used as a glidant intableting. When the granules are hydrated and/or partially melted, thephysical characteristics of the granules change a great deal. Themicrostructure of hydrated starch granules obtains a very rigid andstable crystallized core with a hydrated outer layer that can resemble amicroscopic gel. The gel can vary from a very thin, nearly crystallizedcore to an extremely soft and sticky exterior outer boundary. While notwishing to be limited by theory, it is believed particles become coatedwith the sticky starch granules, preventing them from packing tightlywith each other. This mechanism is believed to prevent large particlesfrom forming hard cakes in vehicles of the present invention.Preferably, embodiments of the invention allow for easy and quickresuspension of the active ingredient after the initial compounding inthe vehicle of the invention. In an embodiment, a drug or inactiveingredient can be suspended or resuspended in a vehicle of the inventionwithout high shear mixing.

C. Physiological Compatibility

Physiologically mismatched compositions can arise from the basicbiochemical nature of a vehicle, including osmolality, pH, and sugar(carbohydrate) content. Failure to match the osmolality or pH of aliquid medication to a patient's needs, for example, can result in amedication that is not compatible with a patient. Ingestion of amedication that is hyperosmotic, for example, can result in a quickrejection of the medication by the patient and failure of the treatment.

An important aspect of a vehicle for preparing medicinal suspensions orsolutions is osmolality/osmolarity. Osmolarity is the number of solutemolecular entities (non-ionizing molecules count as one each, whereasmolecules that ionize into n particles when dissolved in watercontribute n times their count) per unit volume. Physicians,pharmacists, and nutritionists more frequently refer to osmolality,which is the number of solute molecular entities per unit mass, and isindependent of temperature. The use of these terms is roughlyinterchangeable as the difference in osmolality and osmolarity attemperatures from 0° C. to 100° C. is less than 5% at the limit ofinfinite dilution, which is about 550 mOsmol.

Blood serum has an osmolality of about 300 mOsmol per kilogram (mOsmol)(Seeley, et. al., Anatomy & Physiology 2nd Ed., Allan et al. eds.,Mosby-Year Book Inc., St. Louis, Mo., 1992, p. 863). Compoundedpreparations with high osmolarity (above approximately 300 mOsmol)(http://uthealthinformatics-net/docs/english/ma/hyperosm_ma.asp) aredehydrating when taken orally. When a hyperosmotic preparation isingested by a patient, water is drawn from the “third space” surroundingthe gut (comprised primarily of the small and large bowels) into thelumen of the gut by osmolar pressure until the material in the digestivetract reaches the same osmolality as the surrounding body fluid. Thishyperosmotic effect is known as saline laxation and results in somelevel of dehydration for the patient. Infants, small children, and theelderly are most sensitive to this dehydration. In these sensitivepatients, the net flow of water into the lumen of the gut can cause acycle of diarrhea. As the patient tries to maintain hydration bydrinking more water or other hypotonic liquid, bulk laxation can betriggered.

We have surprisingly found that suspending agents comprising apolysaccharide having at least 50% glucose repeating saccharide unitsand at least 90% alpha linkages are more physiologically compatible topatients than the typical derivatized cellulosic-based suspending agentsthat are most common in conventional liquid vehicles. Celluloses andderivatized celluloses are non-nutritive, cannot be readily metabolizedby the body, and tend to be recognized as foreign materials by the body.

FLAVOR-SWEET™ (HUMCO, Texarkana, Tex.), a sweetening vehicle, andFLAVOR-PLUS™ (HUMCO, Texarkana, Tex.), a suspending vehicle, designed tobe mixed in an approximately one-to-one ratio in the final compoundedproduct and ORA-SWEET® (Paddock Laboratories, Minneapolis, Minn.), asweetening vehicle, and ORA-PLUS® (Paddock Laboratories, Minneapolis,Minn.), which are also designed to be mixed in an approximately 1:1ratio in the final compounded product, are hyperosmotic (theoreticalvalue of approximately 1700 mOsmol, calculation based on informationfrom the manufacturer's literature) and the cellulosic-based suspendingagents can act as a laxative. Another product, Roxane's diluent(flavored) (Roxane Laboratories, Columbus, Ohio), uses PEG-8000 as aviscosity increasing agent. PEG-8000 imparts a bitter flavor note to amedicinal preparation, which is masked in the raw preparation but islikely to form chords with other bitter flavor notes introduced by theincorporation of a variety of drugs. PEG-8000, like the suspendingagents in FLAVOR-PLUS and ORA-PLUS for example, has a mild to moderatelaxative effect.

Cellulosic suspending agents contain beta linkages between the repeatingsaccharide units. Beta linkages, unlike alpha linkages, are indigestibleby humans. As a result, cellulosic suspending agents can act like bulklaxatives. In contrast, starches are typically linear or branchedpolysaccharides. The bonds between the carbohydrate monomers in starchcan be split readily by biologically active enzymes resulting in mono-,di- and tri-saccharide that are quickly absorbed and metabolized.

The human body is more efficient with the ingestion of hypoosmoticmaterials (Remington: The Science and Practice of Pharmacy, Genarro A.R. ed., 20^(th) ed., Lippincott Williams & Wilkins, Philadelphia, Pa.,2000, pp. 744, 321). When a hypoosmotic material is ingested, the flowof water is from the lumen of the gut into the third space providing anet hydrating effect and keeping the gut “dry”. Vehicles of theinvention can be prepared with very low osmolality. This aspect of theinvention enables a compounding pharmacist, for example, to add drugsand/or inactive ingredients in significant concentrations withoutconcern about hypertonicity in the final preparation. In someembodiments, the osmolality of the vehicle of the invention is 300mOsmol or less, more preferably 200 mOsmol or less, more preferably 100mOsmol or less, more preferably 50 mOsmol or less, more preferably 20mOsmol or less. In an embodiment, the osmolality of a vehicle of theinvention is from about 30 mOsmol to about 40 mOsmol. In anotherembodiment, the osmolality of a vehicle of the invention is from about20 mOsmol to about 30 mOsmol. In some embodiments, the osmolality of avehicle of the invention is sufficiently low to allow the addition of adrug(s) and inactive ingredients without the osmolality of the finalpreparation exceeding 300 mOsmol.

In order to obtain physiological compatibility with a patient, we havealso carefully controlled the carbohydrate or natural sweetener contentin some embodiments of the invention. A vehicle of the invention can besweetened, for example, with an artificial sweetener and maintain anosmolality of 300 mOsmol or less. The artificial sweetener can benutritive or non-nutritive. Preferably, the artificial sweetener is apotent sweetener, such as sucralose. A potent artificial sweetenerallows for the use of less sweetener, resulting in lower osmolality. Inan embodiment, a vehicle of the invention contains less than 1%,preferably less than 0.1% w/v, more preferably less than 0.075% w/vartificial sweetener.

Sweetening a vehicle of the invention with an artificial sweetener canalso make the vehicle compatible with a patient having blood glucosesensitivity. For example, patients with diabetes are sensitive tofactors that change their blood glucose level. Even patients withoutdiabetes can suffer adverse effects from sudden changes in their bloodglucose levels. The blood glucose level is sensitive to the compositionof substances taken orally. It is well established that simple sugarsand small metabolizeable molecules can cause a spike in the bloodglucose level of these individuals. Currently available products rely onnatural sugars or reduced sugars for both their texture and sweetness.Reducible sugars can cause blood glucose reactions similar to naturalsugars. The ingested medication combined with currently availablevehicles containing natural sugars or reduced sugars can drasticallyalter blood glucose levels, especially in tightly managed patients.

D. Uses

There is often a need to administer solid medications orally in liquidforms to patients. These patients include adults who cannot swallowsolid dosage forms, infants or children, nonambulatory patients withnasogastric tubes, geriatric patients, and animals Likewise, patientssuffering from severe oral traumas or disease could use the vehicles ofthe invention to ease ingestion of a desired medication. Patientsrecovering from severe oral trauma, such as mandibular fracture orcomplex dental procedures, have dysphagia. An embodiment of theinvention would ease the transit of the medication from the oral cavitythrough the pharynx to the esophagus and eventually to the stomach.

The aqueous suspending vehicles of the invention can be combined with adrug, medication, or medicament to form a treatment for a variety ofdiseases or disorders. Such diseases or disorders include, but are notlimited to, cellular hypoproliferation, neoplastic diseases,inflammatory diseases, multiple sclerosis, myocarditis, sinusitis,eczema, periodontal disease, kidney disease and Type 1 diabetes. Thesediseases are representative; many other diseases or disorders may betreated.

Many drugs or medicaments can be used in the aqueous suspending vehiclesof the invention. Starch is known to be a broadly compatible excipientand a binding agent for tablets. The compatibility of starches with manydrugs in the presence of water is well established, as many commercialtablets are prepared by wet granulation methods, usually with a starchcomponent. See, for example, U.S. Pat. No. 6,238,695 andhttp://webusers-xula-edu/tmandal/pharmaceutics/TABLET-ppt). Starch alsohas a long history in food chemistry, further highlighting itscompatibility and stability with the plethora of chemical entitiespresent in all manner of food preparations.

Many liquid or solid drugs and medicaments can be suspended in thevehicle of the invention and administered to a patient. A patient may bea human or an animal. In preferred embodiments, the drug or medicamentis a solid or liquid oral dosage form. Some drugs have aqueousintolerance and, as such, should be mixed and administered with littletime delay. In some embodiments, the drug is suitable for delivery in anaqueous vehicle. The following are exemplary, non-limiting drugs thatcan be used in the invention. These drugs include hydrochlorothiazide,cyclosporin, cimetidine, captopril, amoxicillin, acetaminophen,ibuprofen, ranitidine, tetracyclines, vitamin or vitamin supplements,and cephalexin and related compounds. This list is not exhaustive, butcontains a number of representative examples. Most drugs in oral dosageform that are useful for treating patients by pharmacists or physiciansor other caregivers can be administered using the liquid vehicle of theinvention.

In a typical preparation, a drug or medicament available in a tablet orbulk powder form is finely ground, wetted with a wetting agent, and thencombined slowly with a liquid vehicle. A vehicle of the invention can becombined with about 0.01 to about 100,000 mg of drug or inactiveingredient per 100 ml of vehicle. The drug or inactive ingredient can bein the form of a liquid, powder, tablet, or capsule. Tablets or capsulesare typically ground to a powder before they are combined with thevehicle. In an embodiment, the concentration of the drug is about 1 toabout 100 milligrams per 100 ml of the vehicle of the invention. Thistechnique is flexible and provides a method to treat a patient with avariety of medicaments in an alternative dosage form.

EXAMPLES

The present invention may be better understood with reference to thefollowing examples. These examples are intended to be representative ofspecific embodiments of the invention and are not intended as limitingthe scope of the invention.

In some of the examples, an embodiment of the invention containing astarch suspending agent is evaluated in side-by-side testing with a 1:1mixture of ORA-SWEET SF® and ORA-PLUS® (Paddock Laboratories,Minneapolis, Minn.). ORA-SWEET SF® is an example of a sweetening vehicleand contains the nutritive sweetener sorbitol. ORA-PLUS® is an exampleof a suspending vehicle and contains the α-glycan cellulosic suspendingagents microcrystalline cellulose, sodium carobxymethylcellulose, andxanthan gum. ORA-SWEET SF® and ORA-PLUS® are designed to be mixed in anapproximately 1:1 ratio in the final compounded product. The 1:1 mixtureof ORA-SWEET SF® and ORA-PLUS® was prepared in all examples according tothe manufacturer's directions. The 1:1 mixture of ORA-SWEET SF® andORA-PLUS® is hereinafter referred to as “OO” in the examples.

Example 1

An embodiment of the liquid vehicle of the invention contains thefollowing ingredients:

TABLE 2 Ingredient Quantity (g) (w/w % relative to water) PURE-GEL ® 994884.9 4.25 Sucralose 15.615 0.075 Simethicone 0.2082 0.001 SodiumBenzoate 12.43 0.060 Citric Acid 8.09 0.039 Distilled Water 20820

The embodiment shown in Table 2 (available commercially as SYRSPEND™ SF(Gallipot, St. Paul, Minn.)) was prepared with standard amylaseprevention measures. To produce the above embodiment, the starchsuspending agent PURE-GEL® 994(884.9 g; Grain Processing Corp.,Muscatine, Iowa), simethicone (0.2082 g), sodium benzoate (12.43 g), and75% of the distilled water (15615 g) were combined in a single vesseland heated to between 95° C. and 100° C. with constant stiffing for 30minutes. The heated mixture was cooled with continuous stiffing to atleast 40° C. and then cool water was added to bring the volume of thecooled mixture to the pre-heating volume. The citric acid (8.09 g) andsucralose (15.615 g) was dissolved in sufficient water to completesolubilization. This solution was added with stiffing to the cooledmixture, along with the remaining distilled water. The batch size of theliquid vehicle was 20820 g (in grams water).

The process produced a cloudy liquid with a syrupy texture that had atotal theoretical osmolality of 23.3 mOsmol. The osmolality of theliquid vehicle shown in

Table 2 was determined experimentally by Advanced Instruments, Inc.(Norwood, Mass.) with a model 3D2 quality control osmometer and a model210 Osmometer (Advanced Instruments, Norwood, Mass.). The model 3D2osmometer was calibrated with five 100 mOsm/kg H₂O and five 900 mOsm/kgH₂O laboratory standards (Advanced Instruments, Norwood, Mass.) and thenthe osmolality of ten 250 μl samples of the liquid vehicle was measuredwith the calibrated osmometer. The model 210 osmometer was calibratedwith three 50 mOsm/kg H₂O and three 850 mOsm/kg H₂O laboratory standards(Advanced Instruments, Norwood, Mass.) and then the osmolality of ten 20μl samples of the liquid vehicle was measured with the calibratedosmometer. The liquid vehicle had experimental osmolality of 36 to 39mOsmol (data not shown).

Example 2

An embodiment of the liquid vehicle of invention contains the followingingredients:

TABLE 3 (w/w % relative Ingredient Quantity (g) Quantity (g) to water)PURE-GEL ® 994 936.9 4.5 Sucralose 15.615 0.075 Simethicone 0.2082 0.001Benzole Acid 10.2902 0.049 Sodium Benzoate 12.4251 0.060 Buffer 44.00310.211 Malic Acid 7.6372 Citric Acid 11.5714 Sodium Citrate 24.7945 Total44.0031 Distilled Water 20820

The embodiment shown in Table 3 was prepared with standard amylaseprevention measures. To produce the above embodiment, the starchsuspending agent PURE-GEL® 994(936.9 g; Grain Processing Corporation,Muscatine, Iowa), simethicone (0.2082 g), benzoic acid (10.2902 g),sodium benzoate (12.4251 G), and 75% of the distilled water (15615 g)were combined in a single vessel and heated to between 95° C. and 100°C. with constant stirring for 30 minutes. The heated mixture was cooledwith continuous stiffing to at least 40° C. and then cool water wasadded to bring the volume of the cooled mixture to the pre-heatingvolume. The buffer and sucralose (15.615 g) was dissolved in sufficientwater to complete solubilization. This solution was added with stiffingto the cooled mixture, along with the remaining distilled water. Thebuffer was a batch mixture of malic acid, citric acid, and sodiumcitrate in the proportions described in Table 3. The batch size of theliquid vehicle was 20820 g (in grams water). The process produced acloudy liquid with a syrupy texture that had a total theoreticalosmolality of 37.0 mOsmol.

Example 3

An embodiment of the liquid vehicle of the invention contains thefollowing ingredients:

TABLE 4 (w/w % relative Ingredient Quantity (g) Quantity (g) to water)INSCOSITY ™ 658 1135.6 5.0 Sucralose 17.03 0.075 Simethicone 0.227 0.001STABILITE ™ SD30 2271 10.0 Benzole Acid 8.59 0.1 (total benzoate) SodiumBenzoate 14.12 0.1 (total benzoate) Sorbic Acid 22.71 0.1 Buffer 48.000.211 Malic Acid 7.613 Ascorbic Acid 10.000 Citric Acid 5.672 SodiumCitrate 24.714 Total 48.00 Distilled Water 22712

The embodiment shown in Table 4 was prepared with standard amylaseprevention measures. To produce the above embodiment, the starchsuspending agent INSCOSITY™ 658 (1135.6 g; Grain Processing Corp.,Muscatine, Iowa), simethicone (0.227 g), the sorbic acid (22.71 g), thebenzoic acid (8.59 g), the sodium benzoate (14.12 g), and 75% of thedistilled water (17034 g) were combined into a single vessel and heatedto between 80° C. and 85° C. with constant stiffing for 5 minutes. Theheated mixture was cooled with continuous stirring to at least 40° C.Sucralose (17.03 g), STABILITE™ SD30 (2271 g; SPI Polyols, New Castle,Del.), and the buffer (48 g) were dissolved in sufficient water tocomplete solubilization. This solution was added with stirring to thecooled mixture, along with the remaining distilled water. The buffer wasa batch mixture of malic acid, ascorbic acid, citric acid, and sodiumcitrate in the proportions described in Table 4. The batch size of theliquid vehicle was 22712 g (in grams water).

The process produced a liquid with a syrupy and sticky texture that hada theoretical osmolality of 185 mOsmol. The above embodiment can beproduced without heating as the INSCOSITY™ starch is pre-hydrated. Insuch an embodiment, the first mixing step is carried out at roomtemperature (20° C. to 25° C.) with constant stirring until the sorbicacid and benzoic acid are completely dissolved. Heat was applied in theprocess described above to simply speed the dissolution of the sorbicacid and benzoic acid.

Example 4 Chemical Perturbations Do Not Thin a Vehicle Containing aStarch Suspending Agent

A vehicle for preparing a medicinal suspension should maintain its formand function after perturbation by a variety of factors. Conditions thataffect the form and function of a suspending vehicle include, but arenot limited to, ionic strength, Lewis acidity/basicity, and freezing andheating. We assessed the impact of these chemical perturbations on theviscosity of a vehicle containing a starch suspending agent (vehicle ofExample 1 (VE1) and a vehicle containing microcrystalline cellulose andcarboxymethycellulose suspending agents (OO). This example demonstratesthat a vehicle containing a starch suspending agent is less sensitive tofreezing/heating perturbations than a vehicle containingmicrocrystalline cellulose and carboxymethycellulose suspending agents.

Methods

The viscosity of OO or the vehicle of Example 1 was measured before andafter the addition of potassium bromide, aluminum chloride, or EDTAdisodium salt. The viscosity was measured with Brookfield RVDV-III Ultrarheometer from Brookfield Engineering Laboratories, Inc., Middleboro,Mass., using the small sample adapter with spindle SC4-21 at 100 RPM.The potassium chloride (0.36 g) aluminum chloride (0.40 g), or EDTAdisodium salt (1.12 g) was added to 10 ml of OO or the vehicle ofExample 1 and the vehicle was shaken for 5 minutes. The vehicle wasallowed to stand for 30 minutes and then the viscosity of the vehiclewas measured.

The viscosity of OO or SS was also measured before and after afreeze-heat cycle using Brookfield RVDV-III Ultra rheometer with aSC4-21 spindle/small sample adapter at 100 RPM (Brookfield EngineeringLaboratories, Inc., Middleboro, Mass.). All measurements were carriedout at 22° C. ±2° C. Ten ml of OO or SS was frozen, heated in a waterbath to 80° C., refrozen, heated in a water bath to 80° C., and thenallowed to cool to 22° C. ±2° C. The viscosity of the vehicle wasmeasured once the vehicle cooled to 22° C.±2° C.

Results

The results of the experiment are shown in Table 5. The vehiclecontaining microcrystalline cellulose and carboxymethycellulosesuspending agents (OO) was sensitive to the freeze-heat perturbation,whereas the vehicle containing a starch suspending agent (VE1) was not.OO thinned significantly (approximately 10%) percent after thefreeze-heat cycle. In contrast, the VE1 thickened slightly after thefreeze-heat cycle. The ionic strength, Lewis acid, and Lewis baseperturbations did not significantly affect the viscosity of OO. TheLewis base perturbation did not significantly affect the viscosity ofVE1. VE1 thickened slightly after ionic strength perturbation andthinned slightly after Lewis acid perturbation. This loss of viscosityis minor as the viscosity of VE1 is sufficiently high, as shown inExample 5, to maintain particles in suspension.

TABLE 5 Vehi- Probed g/10 mL Starting Final cle Perturbation Chemicalvehicle Viscosity Viscosity OO Ionic Potassium 0.36 54.0 54.5 StrengthBromide VE1 Ionic Potassium 0.36 184.5 207.0 Strength Bromide OO LewisAcid Aluminum 0.40 54.0 53.0 Chloride VE1 Lewis Acid Aluminum 0.40 184.5173.0 Chloride OO Lewis Base EDTA, 1.12 54.0 53.5 disodium salt VE1Lewis Base EDTA, 1.12 184.5 182.0 disodium salt OO Freeze-Heat Freeze,Heat N/A 54.0 50.5 in Water bath, cool to 22° C. ± 2° C. (2x) VE1Freeze-Heat Freeze, Heat N/A 184.5 237.0 in Water bath, cool to 22° C. ±2° C. (2x).

Example 5 Suspendability of Drugs in a Vehicle Containing a StarchSuspending Agent

Suspendability of insoluble ingredients and resuspendability ofinsoluble ingredients that have sedimented are important characteristicsfor a compounding vehicle.

Insoluble pharmaceutically active or inactive ingredients in asuspending vehicle can sediment with time. Sedimentation of theseingredients results in heterogeneous preparations of the incorporatedactive or inactive pharmaceutical ingredients, which if not vigorouslyshaken, can result in inaccurate dosing. The risk of inaccurate dosingis reduced the longer a vehicle can maintain insoluble pharmaceuticalingredients in suspension.

The suspendability of five different drugs was evaluated in a vehiclecontaining a starch suspending agent (vehicle of Example 1 (VE1)) and avehicle containing microcrystalline cellulose and carboxymethycellulosesuspending agents (OO). This example demonstrates that a vehiclecontaining a starch suspending agent maintained each of the five drugsin suspension for 7 days with minimal sedimentation. In contrast, two ofthe five drugs settled significantly in the vehicle containingmicrocrystalline cellulose and carboxymethycellulose suspending agents.

Methods

Suspensions of baclofen, bethanechol chloride, labetalol hydrochloride,verapamil hydrochloride, or ibuprofen were prepared in VE1 or OO.Commercially available tablets were ground in a tablet grinder(Gallipot, Inc., St. Paul, Minn.; Item# 101132) to a fine powder andwetted with a minimal quantity of propylene glycol. The wetted powderwas incorporated into 50 ml VE1 or OO by geometric dilution and storedin individual non-opaque containers. Table 6 shows the number of tabletsadded to VE1 or OO and the concentration of drug per ml of VE1 or OO.The concentrations of the pharmaceutical compounds in suspensionrepresent ‘typical’ prescribed preparations.

TABLE 6 Number of Concentration of Drug Drug Name Tablets/50 ml (mg/mL)Baclofen 50  10 Bethanechol Chloride 5 5 Labetalol Hydrochloride 7 42Verapamil Hydrochloride  31¼ 50 Ibuprofen  1¼ 20

The suspensions were evaluated immediately after preparation withrespect to ease of preparation, homogeneity, and viscosity by thepharmaceutical technician preparing the suspensions. The suspensionswere rated on a subjective scale of 0-10: ease of preparation,0=difficult, 10=very easy; homogeneity, 0=drug settles completely andimmediately, 10=consistently homogenous in appearance along the verticalaxis; viscosity, 0=water, 10=thick molasses.

The suspensions were stored in the dark at room temperature for 7 daysand then settling of the drugs and resuspendability of sedimented drugin OO or VE1 was evaluated. Settling and resuspendability of the drugswas rated on a subjective scale of 0-10: settling (how much productapparent at bottom of container, 10=none, 0=all); resuspendability (howhomogenous does the product appear after moderate shaking, 10=perfectlyhomogenous, 0=not homogenous (heterogeneous)). Resuspendability ofsedimented ingredients was evaluated after evaluation of settling. Thesuspensions were shaken deliberately (stepwise), with frequentinspections of the bottom of the container.

Results

The results for ease of preparation, homogeneity, and viscosity aresummarized in Table 7.

TABLE 7 Ease of Preparation Homogeneity Viscosity Drug VE1 OO VE1 OO VE1OO Baclofen 10 9 9 9 7 6 Ibuprofen 10 10 9 9 7 4 Labetalol Hydrochloride8 1 9 3 7 1 Bethanechol Chloride 10 10 9 9 7 5 Verapamil Hydrochloride10 3 9 8 7 2

VE1 preparations were generally rated as easier to prepare than the OOpreparations by a pharmaceutical technician (average 9.6, 0.89 standarddeviation (SD) vs. average 6.6, 4.28 SD) VE1 preparations wereconsistent with respect to homogeneity of the prepared suspensions(average 9, 0.0 SD). The opaque nature of VE1, however, may have maskedsome of the heterogeneity in the distribution of the drug. OOpreparations demonstrated greater variability in homogeneity (average7.6, 2.61 SD). In preparations of labetol hydrochloride and verapamilhydrochloride in OO, there appeared to be a phase separation of thesuspending agent from the liquid phase. The viscosities of the VE1preparations were consistent (average 7, 0.0 SD). The viscosity ofcontrol VE1 (VE1 prior to the addition of any of the drugs) wasevaluated as 7. The viscosity of the OO preparations was variable(average 3.6, 2.07 SD). The viscosity of control OO (OO prior to theaddition of any of the drugs) was evaluated as 6. Much of thevariability in the viscosity of the OO preparations can be attributed tothe phase separation observed in the labetol hydrochloride and verapamilhydrochloride preparations. In the OO preparations in which phaseseparation was observed, a sharp decrease in viscosity relative to thecontrol OO was apparent.

The results for settling and resuspendability of sedimented ingredientsare summarized in Table 8.

TABLE 8 Settling Resuspendability Drug VE1 OO VE1 OO Baclofen 8 6 9 9Ibuprofen 8 7 9 9 Labetalol Hydrochloride 9 2 9 3 Bethanechol Chloride 86 9 9 Verapamil Hydrochloride 7 2 9 6

The vehicle containing a starch suspending agent (VE1) maintained eachof the five drugs in suspension for 7 days with minimal sedimentation.The drugs easily were resuspended in VE1 after settling. The vehiclecontaining microcrystalline cellulose and carboxymethycellulosesuspending agents (OO) maintained three of the five drugs in suspensionfor 7 days. Baclofen, ibuprofen, and bethanechol chloride were suspendedin OO after 7 days with minimal to moderate sedimentation. A largeportion of the labetalol hydrochloride and verapamil hydrochloride hadsettled in the OO after 7 days. Baclofen, ibuprofen, and bethanecholchloride were easily resuspended in OO after settling. Labetalolhydrochloride and verapamil hydrochloride were more difficult toresuspend in OO after settling.

Example 6 Resuspendability of Calcium Carbonate in a Vehicle Containinga Starch Suspending Agent

Some pharmaceutically active or inactive ingredients can form cakes atthe bottom or top of a liquid vehicle (depending on density) that aredifficult to resuspend with shaking. Calcium carbonate (precipitated,heavy) is a particularly challenging compound to resuspend in a liquidvehicle. Calcium carbonate is dense and hydrophilic, therefore itminimally interacts with suspending agents and forms cakes in manysuspending vehicles that are difficult to resuspend. The particle sizedistribution of calcium carbonate is also larger than many drugpreparations.

The resuspendability of calcium carbonate in a vehicle containing astarch suspending agent (vehicle of Example 1 (VE1)) and a vehiclecontaining microcrystalline cellulose and carboxymethycellulosesuspending agents (OO) was evaluated. This example demonstrates thatcalcium carbonate is more easily resuspended in a vehicle containing astarch suspending agent than in a vehicle containing microcrystallinecellulose and carboxymethycellulose suspending agents.

Methods

Five ml of VE1 or OO was added to a 12×75 mm test tube. Five hundred mgof calcium carbonate (precipitated, heavy) was added to each tube andthe tubes were vigorously shaken for three minutes at room temperature.The test tubes were then covered, set upright in a beaker, and allowedto stand undisturbed for 16 hours at room temperature. The test tubeswere then gently inverted and reoriented to an upright position fivetimes. After the fifth inversion cycle, the test tubes were subjected tovigorous shaking, one shake at a time. The size of the cake in the testtubes was observed after each inversion cycle or shake and recorded. Thesize of the cake was rated on a qualitative scale from 0 to 10, with 0representing no observable cake and 10 representing the quantity of cakeobserved in the OO preparation before the first inversion cycle.

Results

The results of the experiment are shown in Table 9. Calcium carbonatewas more easily resuspended in a vehicle containing a starch suspendingagent (VE1) than a vehicle containing microcrystalline cellulose andcarboxymethycellulose suspending agents (OO). When the calcium carbonatewas first added to the vehicle samples, OO did not wet the calciumcarbonate as easily or as quickly as the vehicle of Example 1. Thisobservation was not unexpected as OO has a higher osmolality than thevehicle of Example 1.

TABLE 9 Repetition # VE1 OO Inversion 1 8 10 Inversion 2 6 9 Inversion 35 8 Inversion 4 3 7 Inversion 5 2 7 Shake 1 1 5 Shake 2 1 5 Shake 3 1 4Shake 4 0 3 Shake 5 0 3 Shake 6 0 2 Shake 7 0 1 Shake 8 0 0

Example 7 Rheology of a Vehicle Containing a Starch Suspending Agent

The rheology of a liquid vehicle is important to both the suspending andhandling properties of the vehicle. A liquid suspending vehicle ideallyis a pseudoplastic power law fluid with a low flow index or has ameasurable yield value (Thompson, J. E., Davidow L. A Practical Guide toContemporary Pharmacy Practice, 2^(nd) ed., Lippincott Williams &Wilkins, Baltimore, Md., 2004, p. 28.1-28.23). Power law fluids withflow indexes less than 1 are pseudoplastic. The closer the flow index isto zero, the greater the viscosity at low shear rates. At the shearrates generated by sedimentation, the flow index of a suspending vehicleideally decreases as the shear rate decreases. Another importantrheological characteristic of a liquid vehicle is thixotropy. A liquidsuspending vehicle ideally is thixotropic, meaning the viscosity of thevehicle increases as the vehicle sits undisturbed (Thompson, J. E.,Davidow L. A Practical Guide to Contemporary Pharmacy Practice, 2^(nd)ed., Lippincott Williams & Wilkins, Baltimore, Md., 2004, p.28.1-28.23).

The rheology of a vehicle containing a starch suspending agent (vehicleof Example 1 (VE1)) and a vehicle containing microcrystalline celluloseand carboxymethycellulose suspending agents (OO) was compared. Thisexample demonstrates that the vehicle containing a starch suspendingagent is thixotropic and has higher viscosity than the vehiclecontaining microcrystalline cellulose and carboxymethycellulosesuspending agents at shear rates generated by sedimentation.

Methods

All rheology measurements were carried out with a Brookfield RVDV-IIIUltra rheometer (Brookfield Engineering Laboratories, Inc., Middleboro,Mass.). Viscosity and shear stress and shear rate measurements wereanalyzed with Rheocalc32 software, version 2.6.0.32 (BrookfieldEngineering Laboratories, Inc., Middleboro, Mass.). Static yield valuemeasurements were analyzed with EZ-Yield software, version 1.0.2.17(Brookfield Engineering Laboratories, Inc., Middleboro, Mass.).Viscosity, shear stress, and shear rate measurements were obtained usinga small sample adapter with spindle SC4-21 (Brookfield EngineeringLaboratories, Inc., Middleboro, Mass.). Static yield value measurementswere obtained using vane spindles, which are identified by their numberin the specific experiments. All measurements were carried out at 22°C.±2° C.

As the RPM of the instrument is the independent variable for theexperiments, its exact value is specified with each experiment. Notethat while the RPM is the controlled parameter, we report shear rate asthe independent variable, since it is the physical quantity beingcontrolled (and is directly related to RPM), and is not dependent on theparticular instrument.

Results

FIG. 1 shows a scan of shear rates ranging from 0.1 to 100, with the logof the shear rates being evenly spaced to minimize sampling error forthe power law modeling. In this experiment, the RPMs were varied from0.1 to 100 RPMs, with data points chosen such that the log of the shearrates gave 30 equally spaced values. The vehicle containing a starchsuspending agent (VE1) and the vehicle containing microcrystallinecellulose and carboxymethycellulose suspending agents (OO) were held atthe indicated shear rate long enough to provide a stable reading on theinstrument. Deviations from the linear fit lines are indications of thefluids having non-ideal power law behavior. VE1 had an upward curve atlow shear rates indicating that the flow index is decreasing as theshear rate increases. In contrast, OO had a downward curve indicatingthat the flow index is increasing as the shear rate increases

FIG. 2 shows a scan of shear rates ranging from 0.1 to 1, which is nearthe limit of the rheometer. In this experiment, the RPMs were variedfrom 0.01 to 1, in 20 evenly spaced values. The vehicle containing astarch suspending agent (VE1) and the vehicle containingmicrocrystalline cellulose and carboxymethycellulose suspending agents(OO) were held at the indicated shear rate long enough to provide astable reading on the instrument. VE1 had an upward curve at low shearrates, indicating that the flow index is decreasing as the shear rateincreases. In contrast, OO had a downward curve indicating that the flowindex is increasing as the shear rate increases.

FIGS. 1 and 2 demonstrate that the vehicle containing a starchsuspending agent (VE1) has a higher viscosity at all measured shearrates than the vehicle containing microcrystalline cellulose andcarboxymethycellulose suspending agents (OO) and that the flow index ofVE1, in contrast to OO, decreases as the shear rate approaches lowvalues. At the shear rates generated by sedimentation, the viscosity ofVE1 is significantly higher than OO yet the material maintainsworkability and ease of handling for pharmaceutical compounding as thehandling takes place at much higher shear rates.

FIG. 3 shows the results of a rate scan experiment, where the shearstress is measured as the shear rate is steadily increased from itsoriginal value and then decreased to its original value. In thisexperiment, the shear stress was measured at 10, 20, 30, 40, 50, 60, 70,80, 90, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 RPMs, with five secondsat each speed to ensure a stable reading on the instrument. In thisexperimental system, thixotropic fluids display hysteresis due to theshear history of the sample. In FIG. 3, the shear stress of the vehiclecontaining a starch suspending agent (VE1) is plotted against the lefty-axis and the shear stress of the vehicle containing microcrystallinecellulose and carboxymethycellulose suspending agents (OO) is plottedagainst the right y-axis. In contrast to VE1, OO lacks hysteresis. Thedata indicates that VE1, but not OO, is thixotropic.

FIG. 4 shows a thixotropy experiment in which VE1 and OO were allowed toremain undisturbed for varying lengths of time. In this experiment, theVE1 and OO were pre-sheared for 5 minutes at 100 RPM. The spindle wasthen stopped, and 15 seconds elapsed before restarting the spindle speedto 100 RPM. Shear stress was continuously monitored. After 20 seconds ofmeasurement at 100 RPM, the spindle was stopped, and another time periodelapsed before repeating the above measuring protocol. At each ‘waitperiod’, the maximum shear stress was taken as the value for that waitperiod. This does not provide a true measurement of thixotropy as theact of measuring the shear stress requires the sample be stressed, whichdisturbs the sample. Regardless, FIG. 4 demonstrates that vehiclecontaining a starch suspending agent (VE1) thickens with time, whereasthe vehicle containing microcrystalline cellulose andcarboxymethycellulose suspending agents (OO) does not.

Example 8

An embodiment of the liquid vehicle of the invention contains thefollowing ingredients:

TABLE 10 Ingredient Quantity (g) (w/w % relative to water) STA-Rx 1457.47.0 Sucralose 20.82 0.1 Simethicone 0.2082 0.001 Benzole Acid 12.430.060 Distilled Water 20820

The embodiment shown in Table 10 was prepared with standard amylaseprevention measures. To produce the above embodiment, the starchsuspending agent STA-Rx (Tate & Lyle/A. E. Staley, Decatur, Ill.)(1457.4 g), simethicone (0.2082 g), benzoic acid (12.43 G), and 75% ofthe distilled water (15615 g) were combined in a single vessel andheated to between 95° C. and 100° C. with constant stirring for 30minutes. The heated mixture was cooled with continuous stiffing to atleast 40° C. and then cool water was added to bring the volume of thecooled mixture to the pre-heating volume. The sucralose (20.82 g) wasdissolved in sufficient water to complete solubilization. This solutionwas added with stiffing to the cooled mixture, along with the remainingdistilled water. The batch size of the liquid vehicle was 20820 g (ingrams water). The process produced a viscous, semisolid liquid with atotal theoretical osmolality of 15 mOsmol.

The rheology of the embodiment shown in Table 10 was analyzed asdescribed in Example 7. The liquid vehicle was a power law fluid and hada flow index of 0.26 and a consistency index of 18,617 centipoise(Brookfield RVDV-III Ultra, using spindle SC4-21, and measuringviscosities from 0.1 to 10 RPM). The liquid had a static yield value of463 dynes/cm² (Brookfield RVDV-III Ultra, 0.01 RPM, Vane 73, 20 second 6RPM pre-shear interval with 30 second wait time after auto-zeroing at0.5 RPM). The yield value of the liquid vehicle is theoreticallysufficient to suspend 0.5 mm cubes of silver indefinitely. The liquidvehicle was shear thinning (pseudoplastic) and could be poured with asmall amount of agitation (viscosity of about 3700 centipoise at a shearrate of 9.3 sec⁻¹). The thixotropy of this embodiment was not measured,as the yield value was sufficient to give permanent suspensions.

Example 9

An embodiment of the liquid vehicle of the invention contains thefollowing ingredients:

TABLE 11 Ingredient Quantity (g) (w/w % relative to water) Pure Gel 994295 3.900 Sucralose 5.68 0.075 Simethicone 0.0757 0.001 CalciumCarbonate (Light 379 5.000 precipitated, powder) Water 7571

The embodiment shown in Table 11 was prepared with standard amylaseprevention measures. To produce the above embodiment, the starchsuspending agent PURE-GEL® 994 (295 g), simethicone (0.0757 g), and 75%of the distilled water (5678.25 g) were combined in a single vessel andheated to between 95° C. and 100° C. with constant stirring for 30minutes. The heated mixture was cooled with continuous stiffing to atleast 40° C. and then cool water was added to bring the volume of thecooled mixture to the pre-heating volume. The sucralose (15.615 g) wasdissolved in sufficient water to complete solubilization. This solutionwas added with stirring to the cooled mixture, along with the remainingdistilled water. The batch size of the liquid vehicle was 7571 g (ingrams water). The process produced a liquid with a syrupy texture thathad a total theoretical osmolality of 2.5 mOsmol. The pH of the vehicleis approximately 9.8. The calcium carbonate is very sparingly soluble atpH 9.8 (about 0.00012 mol/L) but becomes more soluble (and more activeas a base) as the pH decreases (About 0.01 mol/L at pH 7).

The rheology of the embodiment shown in Table 11 was analyzed asdescribed in Example 7. The liquid vehicle was a power law fluid havinga flow index of 0.76, and a consistency index of 656 centipoise(Brookfield RVDV-III Ultra, using spindle SC4-21, and measuringviscosities from 0.1 to 10 RPM, corrected for dynamic yield value of73.7 dynes/cm²). The vehicle had a static yield value of 107 dynes/cm²,which is theoretically capable of suspending 0.1 mm silver cubesindefinitely (Brookfield RVDV-III Ultra, 0.1 RPM, Vane 72, 20 second 6RPM pre-shear interval with 30 second wait time after auto-zeroing at0.5 RPM). The thixotropy of this embodiment was not measured, since theyield value is sufficient to give permanent suspensions.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and ^(the) include pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to a composition containing “a compound” includes amixture of two or more compounds. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A vehicle for preparing medicinal suspensions or solutions,comprising: a) an aqueous medium; and b) about 1% to about 15% by weightof a suspending agent comprising starch or glycogen; c) an artificialsweetener; d) a pH of about 3 to about 10; e) a buffer comprising anorganic acid, inorganic acid, salts thereof, or mixtures thereof; and f)osmolality of about 300 mOsmol or less; wherein the vehicle isthixotropic and comprises: a yield value greater than 0; or at a shearrate of less than about 1 sec⁻¹, a flow index that decreases or remainsconstant as the shear rate decreases. 2-3. (canceled)
 4. The vehicle ofclaim 1, wherein the starch is a modified starch.
 5. The vehicle ofclaim 1, wherein the starch comprises an amylose to amylopectin ratio ofabout 20%:80% to about 60%:40% by weight.
 6. (canceled)
 7. The vehicleof claim 1, wherein the vehicle comprises a yield value of about 0.01dynes/cm² to about 600 dynes/cm².
 8. The vehicle of claim 1, wherein thevehicle comprises a flow index of less than about 0.8 at a shear rate ofless than about 1 sec⁻¹. 9-10. (canceled)
 11. The vehicle of claim 1,wherein the vehicle comprises a pH of about 3 to about
 5. 12. Thevehicle of claim 1, further comprising: comprising: a) a preservative;b) an antimicrobial agent; c) an anti-oxidant; d) a flavoring agent; e)a flavor enhancer; f) a colorant; g) a texture modifier; h) asurfactant; or i) a defoaming agent.
 13. (canceled)
 14. The vehicle ofclaim 1, wherein the organic acid comprises malic acid, citric acid,ascorbic acid, tartaric acid, adipic acid, lactic acid, furmaric acid,maleic acid, acetic acid, phosphoric acid, a salt thereof, or mixturesthereof.
 15. (canceled)
 16. The vehicle of claim 1, wherein theartificial sweetener comprises sucralose, aspartame, saccharin, stevia,acesulfame-K, or mixtures thereof.
 17. The vehicle of claim 1, whereinthe vehicle comprises about 1% or less artificial sweetener by weight.18. (canceled)
 19. The vehicle of claim 1, wherein the vehicle comprisesosmolality of about 50 mOsmol or less.
 20. The vehicle of claim 1,wherein the vehicle comprises osmolality of about 30 mOsmol to about 40mOsmol. 21-33. (canceled)
 34. The vehicle of claim 1, wherein high shearmixing is not required to uniformly distribute a drug within thevehicle.
 35. A composition comprising the vehicle of claim 1 inadmixture with one or more drugs.
 36. (canceled)
 37. The vehicle ofclaim 1, wherein the vehicle is a pseudoplastic power law fluid andcomprises a consistency index of at least 400 at a shear rate of about 1sec⁻¹.
 38. The vehicle of claim 37, comprising a consistency index ofabout 400 to about 30,000 at a shear rate of about 1 sec⁻¹.
 39. Thevehicle of claim 1, wherein the starch comprises hydrated starchgranules.
 40. The vehicle of claim 1, comprising at least about 70% byweight of the aqueous medium.
 41. A composition comprising: a) asuspending agent comprising starch or glycogen; b) an artificialsweetener; and c) a buffer comprising an organic acid, inorganic acid,salts thereof, or mixtures thereof; wherein the composition, uponaddition of a volume of an aqueous medium, forms a thixotropic liquidvehicle comprising at least 70% aqueous medium by weight, about 1% toabout 15% by weight suspending agent, pH of about 3 to about 10,osmolality of about 300 mOsmol or less, and a yield value greater than 0or, at a shear rate of less than about 1 sec⁻¹, a flow index thatdecreases or remains constant as the shear rate decreases.
 42. Thecomposition of claim 41, wherein the starch comprises an amylose toamylopectin ratio of about 20%:80% to about 60%:40% by weight.
 43. Thecomposition of claim 41, wherein the starch is a modified starch. 44.The composition of claim 41, wherein the organic acid comprises malicacid, citric acid, ascorbic acid, tartaric acid, adipic acid, lacticacid, furmaric acid, maleic acid, acetic acid, phosphoric acid, ormixtures thereof.
 45. The composition of claim 41, wherein theartificial sweetener comprises sucralose, aspartame, saccharin, stevia,acesulfame-K, or mixtures thereof.
 46. The composition of claim 41,further comprising: a) a preservative; b) an antimicrobial agent; c) ananti-oxidant; d) a flavoring agent; e) a flavor enhancer; f) a colorant;g) a texture modifier; h) a surfactant; or i) a defoaming agent.
 47. Acomposition comprising the composition of claim 41 in admixture with oneor more drugs.